ABSTRACT The [unreadable]134.5 protein, present both in herpes simplex virus 1 and 2 (HSV), plays an essential role in viral virulence. Unlike wild-type virus, HSV mutants that lack the [unreadable]134.5 gene are incapable of replicating and causing diseases. However, the underlying mechanisms are not incompletely understood. The major goal of the proposed research is to investigate the biological functions of [unreadable]134.5 during HSV infection. HSV [unreadable]134.5 contains an amino-terminal domain, a linker region of triplet repeats, and a carboxyl- terminal domain. A critical function of [unreadable]134.5 is to block the interferon response mediated by double-stranded RNA dependent protein kinase PKR. In addition, [unreadable]134.5 is involved in virus egress. This activity maps to the amino-terminus of [unreadable]134.5 that shuttles between the nucleus, nucleolus and cytoplasm. It is thought that coordinated actions of functional elements in the [unreadable]134.5 protein and cellular factors facilitate virus egress that contributes to viral virulence. To test this hypothesis, mutational analysis will be performed to define functional modules of [unreadable]134.5. Recombinant viruses will be constructed to study viral replication, spread, and the interferon response in infected cells. Experiments will also be performed to identify targets of [unreadable]134.5. Furthermore, studies will be carried out to explore the molecular nature by which [unreadable]134.5 promotes viral infection. Taken together, these studies will provide insights into the mechanisms of HSV pathogenesis.